Crystalline levosalbutamol sulphate and polymorphic forms thereof

ABSTRACT

The invention provides three polymorphic forms of crystalline levosalbutamol sulphate designated herein as Forms I, II and III. Crystalline levosalbutamol sulphate Form I is characterised by a powder XRD pattern with peaks at 10.8, 11.9, 13.0, 18.3, 28.5±0.2 degrees 2 theta. Crystalline levosalbutamol sulphate Form II is characterised by a powder XRD pattern with peaks at 8.7, 9.6, 15.2, 15.7, 19.1, 27.2, 30.7±0.2 degrees 2 theta. Crystalline levosalbutamol sulphate Form III is characterised by a powder XRD pattern with peaks at 5.5, 6.9, 7.3, 18.7±0.2 degrees 2 theta. Processes for making the new polymorphic forms and pharmaceutical compositions comprising them are also provided.

The present invention relates to crystalline levosalbutamol sulphate,polymorphs thereof, processes for making the crystalline material, andcompositions thereof.

Salbutamol (albuterol) is an antihistaminic compound and is a beta2-adrenoceptor agonist used as a bronchodilator for the treatment ofasthma and as a uterine relaxant for the suspension of premature labour.Salbutamol has been marketed as a racemic mixture, although the beta2-agonist activity resides almost exclusively in the (R)-enantiomer. Theenantioselective disposition of salbutamol and the possibility that(S)-salbutamol has adverse effects have led to the development of anenantiomerically pure (R)-salbutamol formulation known as levosalbutamol(levalbuterol) (Formula I).

A process for the preparation of optically pure salbutamol from monoprotected salbutamol precursor is disclosed in U.S. Pat. No. 5,545,745.

US2004114136 and WO2004052835 describe a process for preparinglevalbuterol L-tartrate in crystalline form; a pharmaceuticalcomposition comprising levalbuterol L-tartrate, in crystalline form; ametered dose inhaler comprising a canister containing an aerosolformulation of levalbuterol L-tartrate in crystalline form; and a methodof affecting bronchodilation in a patient using levalbuterol L-tartrate,including levalbuterol L-tartrate specifically in crystalline form.

Levosalbutamol is prepared by hydrogenating R-benzyl salbutamol in thepresence of palladium on carbon.

R-benzyl salbutamol can be prepared by the process described in U.S.Pat. No. 5,545,745.

The object of the present invention is to provide novel and stablepolymorphic forms of levosalbutamol sulphate named herewith as Form I,Form II and Form III.

Another object of the present invention is to provide processes for thepreparation of these novel polymorphs of levosalbutamol sulphate.

The invention further provides processes for the inter-conversion ofthese forms.

There is also provided crystalline levosalbutamol sulphate (Form I)characterised by a powder XRD pattern with peaks at 10.8, 11.9, 13.0,18.3, 28.5±0.2 degrees 2 theta.

In another aspect, there is provided crystalline levosalbutamol sulphate(Form II) characterised by a powder XRD pattern with peaks at 8.7, 9.6,15.2, 15.7, 19.1, 27.2, 30.7±0.2 degrees 2 theta.

In a further aspect, there is also provided crystalline levosalbutamolsulphate (Form III) characterised by a powder XRD pattern with peaks at5.5, 6.9, 7.3, 18.7±0.2 degrees 2 theta.

The invention also provides various processes for making the novelpolymorphs.

In one aspect, the invention provides a process for preparingcrystalline levosalbutamol sulphate Form I, which process comprises a)preparing levosalbutamol in an organic solvent b) adjusting the pH byaddition of sulphuric acid at from 1 to 10° C. c) isolating the product(Form I) at from 0 to 10° C.

There is also provided a process for preparing crystallinelevosalbutamol sulphate Form I, which process comprises a) dissolvingany form of levosalbutamol sulphate in water b) combining the solutionfrom step a) with a water miscible organic solvent so as to causeprecipitation c) isolating Form I thereon.

The invention also provides a process for preparing crystallinelevosalbutamol sulphate Form II, which process comprises a) dissolvingany form of levosalbutamol sulphate in water b) distilling to residue c)stripping the residue with an organic solvent d) slurrying the solid inan organic solvent e) isolating crystalline Form II.

A further process for preparing Form II comprises jet milling any otherform of levosalbutamol sulphate , for example jet milling crystallineForm I.

In another aspect, there is provided a process for preparing crystallinelevosalbutamol sulphate Form III, which process comprises a) preparinglevosalbutamol in an organic solvent b) adjusting the pH by addition ofsulphuric acid at 25 to 30° C. c) isolating the product (Form III) at 25to 30° C .

In a further aspect, the invention provides a process for preparing FormIII which process comprises a) dissolving any form of levosalbutamolsulphate in water b) combining the solution from step a) with awater-miscible organic solvent so as to cause precipitation c) isolatingForm III therefrom at ambient temperature (25 to 30° C.).

The invention also provides a pharmaceutical composition comprising acompound of the invention and a pharmaceutically acceptable carrier.

The novel compounds, and compositions thereof, are also provided for useas medicaments, particularly in the treatment of respiratory disordersand related conditions.

FIG. 1 shows the X-ray powder diffraction pattern of levosalbutamolsulphate Form I.

FIG. 2 shows an IR spectrum of levosalbutamol sulphate Form I.

FIG. 3 shows the X-ray powder diffraction pattern of levosalbutamolsulphate Form II.

FIG. 4 shows an IR spectrum of levosalbutamol sulphate Form II.

FIG. 5 shows the X-ray powder diffraction pattern of levosalbutamolsulphate Form III.

FIG. 6 shows an IR spectrum of levosalbutamol sulphate Form III.

Table 1 gives the numerical XRD data for FIG. 1 (Form I).

Table 2 gives the numerical XRD data for FIG. 3 (Form II).

Table 3 gives the numerical XRD data for FIG. 5 (Form III).

The present invention provides a novel crystalline form oflevosalbutamol sulphate which is designated as Form I. Levosalbutamolsulphate crystalline Form I is characterized by an X-ray powderdiffraction pattern having significant reflections expressed as 2 thetavalues at about 10.781, 11.941, 13.002, 18.341, 28.541±0.2 degrees, aswill be clear from Table 1.

The X-ray powder diffractogram of levosalbutamol sulphate crystallineForm I is shown in FIG. 1. The major peaks and their intensities ofX-ray powder diffractogram are shown in Table 1. The intensities of thereflections are also expressed as percent of most intense reflection.

Other preferred significant reflections for Form I expressed as 2 thetavalues include 12.66, 15.819, 17.4, 20.939, 21.72, 22.5, 23.14, 24.341,26.12, 31.28, 31.93±0.2 degrees. The X-ray powder diffractograms for allthe polymorphic Forms disclosed herein were collected on Rigaku d-max2200 model X-ray diffractometer using Cu K α radiation (λ=1.5405 A°).

Levosalbutamol sulphate crystalline Form I is also characterised by anIR spectrum with peaks at 3568, 3307, 2980, 2799, 2561, 2458, 1615,1508, 1440, 1380, 1342, 1258, 1200, 1112, 1082, 1029, 976, 915, 836,793, 775, 752, 648, 617, 535, 497, 453 cm⁻¹.

FIG. 2 shows the IR spectrum for Form I. The IR spectra for all thepolymorphic Forms disclosed herein were collected using the Spectrum-Imake of Perkin Elmer Sample and analysed as KBr pellets in the region of4000-400 cm⁻¹.

In the preparation of levosalbutamol sulphate crystalline Form I,preferably R-benzyl salbutamol is hydrogenated using a catalyst,preferably a palladium on carbon catalyst, in a large volume of asuitable organic solvent. Preferably an alcoholic solvent is used, morepreferably ethyl alcohol. Suitably the process is performed underhydrogen pressure, preferably at 30 psi. The catalyst is preferably thenfiltered and the pH of the filtrate is adjusted, preferably to 5-5.5 andpreferably at 0-10° C. with sulfuric acid, suitably concentratedsulphuric acid, to provide crystals, which are filtered and dried toafford levosalbutamol sulphate Form I. The product (Form I) may beobtained by isolating at 0-10° C.

The present invention also provides another novel crystalline form oflevosalbutamol sulphate, which is designated as Form II. Levosalbutamolsulphate crystalline Form II is characterized by an X-ray powderdiffraction pattern having significant reflections expressed as 2 thetavalues at about 8.701, 9.636, 15.180, 15.657, 19.139, 27.199, 30.702±0.2degrees, as will be clear from Table 2.

The X-ray powder diffractogram of levosalbutamol sulphate Form II isshown in FIG. 3. The major peaks and their intensities of X-ray powderdiffractogram are shown in Table 2. The intensities of the peaks areexpressed as percent of most intense reflection.

Other preferred significant reflections for Form II expressed as 2 thetavalues include peaks at about 8.701, 9.636, 15.180, 18.657, 17.44,19.139, 21.699, 22.201, 22.837, 23.339, 23.76, 24.361, 25.022, 25.399,26.059, 26.321, 27.199, 30.702±0.2 degrees.

Levosalbutamol sulphate crystalline Form II is also characterised by anIR spectrum with peaks at 3393, 3026, 2982, 2822, 2463, 1630, 1614,1513, 1484, 1448, 1380, 1321, 1279, 1258, 1235, 1204, 1155, 1093, 1066,1036, 1023, 919, 900, 838, 829, 818, 808, 788, 618, 596, 540, 493, 453,440 cm⁻¹.

FIG. 4 shows the IR spectrum for Form II.

A further aspect of the present invention provides a process for thepreparation of levosalbutamol sulphate crystalline Form II. The processcomprises dissolving any form of levosalbutamol sulphate in water anddistilling it to residue. The residue is further stripped with anorganic solvent, which is preferably water miscible and is preferablyacetone, and the solid further slurried in a solvent, preferably thesame solvent, and isolating the solid, preferably by filtering the solidand drying under vacuum to give levosalbutamol sulphate Form II.

The present invention also provides another novel crystalline form oflevosalbutamol sulphate, which is designated as Form III. Levosalbutamolsulphate crystalline Form III is characterized by an X-ray powderdiffraction pattern having significant reflections expressed as 2 thetavalues at about 5.496, 6.901, 7.340, 18.660±0.2 degrees, as will beclear from Table 3.

The X-ray powder diffractogram of levosalbutamol sulphate Form III isshown in FIG. 5. The major peaks and their intensities of X-ray powderdiffractogram are shown in Table 3. The intensities of the peaks arealso expressed as a percent of the most intense reflection.

Other preferred significant reflections for Form III expressed as 2theta values include peaks at about 5.496, 6.901, 7.340, 8.18, 8.399,10.978, 11.758, 14.298, 16.321, 17.98, 18.18, 18.660, 18.86, 19.189,20.179, 20.72, 20.019, 22.219, 23.121, 23.64, 23.858, 24.638, 25.339,27.62, 28.79, 29.319, 30.80, 32.341, 33.218, 33.781, 34.181±0.2 degrees.

Levosalbutamol sulphate crystalline Form III is also characterised by anIR spectrum with peaks at 3533, 3412, 3086, 2979, 2823, 2799, 1613,1547, 1505, 1437, 1397, 1380, 1365, 1353, 1303, 1256, 1243, 1198, 1110,1133, 1086, 1075, 1055, 1029, 990, 949, 919, 838, 792, 737, 723, 640,618, 563, 536, 480, 442, 425 cm⁻¹.

FIG. 6 shows the IR spectrum for Form III.

A further aspect of the present invention provides a process for thepreparation of levosalbutamol sulphate crystalline Form III. PreferablyR-benzyl salbutamol is hydrogenated using a catalyst, preferably apalladium on carbon catalyst in a suitable organic solvent, preferablyan alcoholic solvent, more preferably ethyl alcohol. Preferably this isdone under hydrogen pressure, preferably at about 30 psi. Form III canbe isolated by adjusting the pH by addition of sulphuric acid at ambienttemperature (25 to 30° C.) and isolating the product at ambienttemperature (25 to 30° C.). Preferably, these steps are done byfiltering the catalyst and washing, for example with denatured alcohol.The pH of the filtrate is preferably adjusted to 5-5.5 at ambienttemperature (25 to 30° C.) with sulfuric acid, preferably inconcentrated form, to give crystals, which are filtered and dried toafford levosalbutamol sulphate Form III. The product (Form III) may beobtained by isolating at 25 to 30° C.

A further aspect of the present invention provides a process for thepreparation of levosalbutamol sulphate crystalline Form II by jetmilling levosalbutamol sulphate. For example, crystalline levosalbutamolForm I may be jet milled so as to give Form II.

It will be understood that crystalline levosalbutamol sulphate and thepolymorphic Forms thereof disclosed herein may be formulated withconventional excipients, auxiliaries and carriers into a wide variety ofpharmaceutical compositions, including but not limited to tablets,capsules, pellets, caplets, MDI, DPI, and Respule formulations, and oralliquids such as syrups. Where appropriate plain or sustained releaseformulations may be provided. Those skilled in the art of pharmaceuticalformulation will be aware of the conventional ingredients which may beemployed to formulate the above compositions. Such formulations may bemade in accordance with conventional manufacturing procedures.

In particular, the compounds of the present invention may be combinedwith one or more other pharmaceutically active compounds, as will beclear to those skilled in the art. Any suitable combination of activematerials is envisaged, provided the combination is acceptable from apharmaceutical and regulatory standpoint. The compounds of the inventionmay, for example be combined with corticosteroids such as fluticasone,beclomethasone or budesonide; anticholinergic agents such asipratropium, tiotropium or atropine; mucolytic agents such as ambroxol;xanthine derivatives such as theophylline; antihistamines; analgesics,and bronchodilators. As will be clear, the additional active or activesmay be provided in any suitable form, including the pharmaceuticallyacceptable derivatives thereof, including salts, esters, polymorphs, andthe optically active forms as well as the racemates.

The invention thus provides a pharmaceutical composition comprisingcrystalline levosalbutamol sulphate, particularly Form I or Form II orForm III thereof, in combination with one or more pharmaceuticallyactive compounds and, optionally, a pharmaceutically acceptable carrier.

The following specific examples illustrate the best mode of carrying outthe process of the present invention. The invention is not limited tothe particular embodiments illustrated herein but includes permutations,which are obvious as set forth in the description.

EXAMPLES Example 1

R-benzyl salbutamol (20.0 kg.), methanol ( 61.0 ltr.), denatured alcohol(72 ltrs.) was charged in an autoclave, palladium (5%) on charcoal (1.30kg) was charged and stirred under 30 psi hydrogen pressure. Aftercompletion of reaction the catalyst was filtered and washed withmethanol (60 lts.) and denatured alcohol (60 ltrs.). The pH of the clearfiltrate was adjusted with sulphuric acid to 5 -5.5 pH at 0-10° C. andthe resulting solid was stirred at 0-10° C. for 1 hr., filtered andwashed with methanol (20 ltrs.). The product was dried under vacuum at30° C. for 1 hr. and further at 50-60° C. for additional 1 hr. to giveR-salbutamol Form I ( 19.0 kg.).

Example 2

R-benzyl salbutamol (10.0 kg.), methanol ( 30.0 ltr.), denatured alcohol(36 ltrs.) was charged in an autoclave, wet palladium (5%) on charcoal(0.65 kg) was charged and stirred under 30 psi hydrogen pressure. Aftercompletion of reaction the catalyst was filtered and washed withdenatured alcohol (25 ltrs.). The pH of the clear filtrate was adjustedwith sulphuric acid to 5-5.5 pH at ambient temperature (25 to 30° C.)and the resulting solid was filtered and washed with methanol (10 ltrs.)at 25 to 30° C. The product was dried under vacuum at 50-60° C. temp togive R-salbutamol sulphate Form III ( 19.0 kg.).

Example 3

R-salbutamol sulphate (14.80 Kg) was dissolved in water (60.0 ltrs.) andfiltered to get a clear solution. The filtrate was distilled undervacuum below 60° C. to residue. The residue was stripped with acetone(74.0 ltrs.) twice, further acetone (148.0 lts.) was added and theresulting slurry was stirred for 2 hrs. The slurry was filtered anddried under vacuum at 60° C. for 10-12 hrs to give R-salbutamol sulphateForm II (11.1 kg.)

Example 4

R-salbutamol sulphate (10 Kg) was dissolved in water (30.0 ltrs.) andstirred for 10-15 min. The resulting clear solution was filtered.Methanol (150 ltrs.) was added slowly to the clear filtrate at roomtemperature and stirred for 30 mins. and further chilled to 0-5° C. Theresulting solid was filtered and washed with methanol. The product wasdried under vacuum at 60° C. for 3-4 hrs to give R-salbutamol sulphateForm I (8 kg.)

Example 5

R-salbutamol sulphate (20 Kg) was dissolved in water (60.0 ltrs.) andfiltered to get a clear solution, charge 300 ltr acetone slowly at25-30° C. and the resulting mixture was stirred for 2 hrs at room temp.The resulting slurry was filtered and dried under vacuum at 80° C. for10-12 hrs to give R-salbutamol sulphate Form III (17 kg.)

Example 6

R-salbutamol sulphate (10 gms) was dissolved in water (30 ml). Methanol(150 ml) was charged at 25-30° C. and Isopropyl alcohol (75ml) was addedand the mixture was cooled to 5-10° C. for 2 hrs. filtered and dried at80° C. under vacuum for 15-20 hrs. to give Form II.

Example 7

R-salbutamol sulphate was dissolved in methanol at reflux temperature.The reaction mass was then cooled to room temperature and furtherchilled to 5-10° C. The resulting solid was filtered and dried at 80° C.to give R-salbutamol sulphate Form II

Example 8

R-salbutamol sulphate Form I was subjected to jet milling to getR-salbutamol sulphate Form II having a particle size of 90% less than 5micron and 100% below 12.5 micron.

Note that in Examples 3 to 7 any form of R-salbutamol sulphate may beused as the stating material. TABLE 1 LEVOSALBUTAMOL S04 - Form I PeakNo. 2θ (deg) d (A) Height Height % FWHM 1 10.781 8.1998 10389 59.5 0.2372 11.941 7.4053 2043 11.7 0.237 3 12.660 6.9865 1090 6.2 0.232 4 13.0056.8036 1080 6.2 0.167 5 15.819 5.5975 1576 9.0 0.266 6 17.400 5.09242170 12.4 0.236 7 18.341 4.8332 2847 16.3 0.268 8 19.019 4.6624 621 3.60.271 9 20.939 4.2390 2564 14.7 0.265 10 21.720 4.0883 3195 18.3 0.28211 22.500 3.9482 2001 11.5 0.202 12 23.140 3.8406 17446 100.0 0.234 1324.341 3.6537 1870 10.7 0.243 14 26.120 3.4087 1108 6.4 0.285 15 28.5413.1249 1379 7.9 0.281 16 31.280 2.8572 914 5.2 0.378 17 31.939 2.7997955 5.5 0.451 18 33.980 2.6361 686 3.9 0.361 19 34.279 2.6138 419 2.40.350 20 35.739 2.51036 712 4.1 0.329 21 36.340 2.4702 635 3.6 0.391

TABLE 2 LEVOSALBUTAMOL S04 - Form II Peak No. 2θ (deg) d (A) HeightHeight % FWHM 1 8.701 10.1542 8249 100.0 0.205 2 9.636 9.1706 2610 31.60.195 3 13.422 6.5914 365 4.4 0.184 4 15.180 5.8318 6090 73.8 0.213 515.657 5.6550 2247 27.2 0.201 6 17.440 5.0809 2091 25.3 0.193 7 19.1394.6335 1416 17.2 0.272 8 19.360 4.5811 900 10.9 0.385 9 19.583 4.5294666 8.1 0.376 10 20.221 4.3879 462 5.6 0.156 11 21.439 4.1413 7819 94.80.256 12 21.699 4.0921 3525 42.7 0.356 13 22.201 4.0008 2317 28.1 0.12814 22.837 3.8907 1299 15.7 0.091 15 23.339 3.8083 4096 49.7 0.308 1623.760 3.7417 2345 28.4 0.236 17 24.361 3.6508 1107 13.4 0.165 18 25.0223.5558 829 10.0 0.080 19 25.399 3.5038 1127 13.7 0.176 20 26.059 3.41661162 14.1 0.271 21 26.321 3.3832 1437 17.4 0.256 22 27.199 3.2759 271832.9 0.255 23 28.740 3.1037 622 7.5 0.193 24 29.263 3.0493 356 4.3 0.62825 30.077 2.9687 721 8.7 0.162 26 30.702 2.9097 1586 19.2 0.211 2731.640 2.8255 631 7.6 0.351 28 32.001 2.7944 700 8.5 0.464 29 32.3192.7677 680 8.2 0.354 30 33.859 2.6452 368 4.5 0.382 31 34.242 2.6165 7308.8 0.315 32 35.002 2.5615 424 5.1 0.244 33 35.299 2.5406 316 3.8 0.54234 35.838 2.5036 376 4.6 0.239 35 36.238 2.4769 427 5.2 0.232 36 36.7372.443 254 3.1 0.313 37 37.999 2.3660 297 3.6 0.245 38 38.265 2.3502 3193.9 0.658 39 38.777 2.3203 491 6.0 0.380

TABLE 3 LEVOSALBUTAMOL S04 - Form III Peak No. 2θ (deg) d (A) HeightHeight % FWHM 1 5.496 16.0657 2337 41.8 0.206 2 6.901 12.799 320 5.70.295 3 7.340 12.034 1938 34.6 0.217 4 8.181 10.7983 2348 42.0 0.645 58.399 10.5187 5559 99.4 0.251 6 10.978 8.0527 577 10.3 0.190 7 11.7587.5203 978 17.5 0.178 8 12.778 6.9221 365 6.5 0.186 9 14.298 6.1895 56510.1 0.233 10 14.701 6.0206 428 7.7 0.165 11 16.321 5.4266 4839 86.50.292 12 16.981 5.2172 498 8.9 0.134 13 17.980 4.9293 1110 19.8 0.319 1418.180 4.8758 1421 25.4 0.532 15 18.660 4.7512 4455 79.6 0.432 16 18.8604.7013 3247 58.0 0.243 17 19.189 4.6215 636 11.4 0.100 18 20.179 4.3969797 14.2 0.529 19 20.720 4.2833 2355 42.1 0.315 20 22.019 4.0335 5594100.0 0.306 21 22.219 3.9976 2598 46.4 0.595 22 23.121 3.8436 761 13.60.563 23 23.640 3.7604 2729 48.8 0.460 24 23.858 3.7265 2189 39.1 0.54725 24.638 3.6103 654 11.7 0.168 26 25.339 3.5120 1235 22.1 0.276 2725.721 3.4607 445 8.0 0.215 28 26.299 3.3859 414 7.4 0.352 29 26.5183.3585 550 9.8 0.354 30 26.879 3.3142 493 8.8 0.249 31 27.620 3.22701316 23.5 0.274 32 28.799 3.0974 719 12.9 0.655 33 29.319 3.0437 82714.8 0.654 34 30.800 2.9006 565 10.1 0.319 35 31.242 2.8606 430 7.70.207 36 32.341 2.7659 867 15.5 0.232 37 33.218 2.6948 719 12.9 0.313 3833.781 2.6512 565 10.1 0.245 39 34.181 2.6211 1029 18.4 0.267 40 36.6462.4502 325 5.8 0.557 41 37.140 2.4187 376 6.7 0.252 42 37.522 2.3950 4788.5 0.306 43 39.397 2.2852 356 6.4 0.427

1. Crystalline levosalbutamol sulphate (Form I) characterised by apowder XRD pattern with peaks at 10.8, 11.9, 13.0, 18.3, 28.5±0.2degrees 2 theta.
 2. Crystalline levosalbutamol sulphate according toclaim 1 substantially as shown in FIG.
 1. 3. Crystalline levosalbutamolsulphate according to claim 1 further characterised by having an IRspectrum substantially as shown in FIG.
 2. 4. Crystalline levosalbutamolsulphate according to claim 1 characterised by a powder XRD pattern withpeaks substantially as shown in Table
 1. 5. Crystalline levosalbutamolsulphate (Form II) according to claim 1 characterised by a powder XRDpattern with peaks at 8.7, 9.6, 15.2, 15.7, 19.1, 27.2, 30.7±0.2 degrees2 theta.
 6. Crystalline levosalbutamol sulphate according to claim 5substantially as shown in FIG.
 3. 7. Crystalline levosalbutamol sulphateaccording to claim 5 further characterised by having an IR spectrumsubstantially as shown in FIG.
 4. 8. Crystalline levosalbutamol sulphateaccording to claim 5 characterised by a powder XRD pattern with peakssubstantially as shown in Table
 2. 9. Crystalline levosalbutamolsulphate (Form III) characterised by a powder XRD pattern with peaks at5.5, 6.9, 7.3, 18.7±0.2 degrees 2 theta.
 10. Crystalline levosalbutamolsulphate according to claim 9 substantially as shown in FIG.
 5. 11.Crystalline levosalbutamol sulphate according to claim 9 furthercharacterised by having an IR spectrum, substantially as shown in FIG.6.
 12. Crystalline levosalbutamol sulphate according to claim 9characterised by a powder XRD pattern with peaks substantially as shownin Table
 3. 13. A process for preparing crystalline levosalbutamolsulphate Form I according to claim 1 which process comprises a)preparing levosalbutamol in an organic solvent b) adjusting the pH byaddition of sulphuric acid at from 0 to 10° C. c) isolating the product(Form I) at from 0 to 10° C.
 14. A process according to claim 13 whereinthe organic solvent is an alcoholic solvent.
 15. A process according toclaim 14 wherein the solvent comprises denatured alcohol or methanol, ora mixture of the two.
 16. A process according to claim 13 wherein instep b) the pH is adjusted to from 5 to 5.5.
 17. A process for preparingcrystalline levosalbutamol sulphate Form II according to claim 5 whichprocess comprises a) dissolving any form of levosalbutamol sulphate inwater b) distilling to residue c) stripping the residue with an organicsolvent d) slurrying the solid in an organic solvent e) isolatingcrystalline Form II.
 18. A process according to claim 17 wherein step a)comprises dissolving crystalline levosalbutamol sulphate Form I or FormIII in water.
 19. A process according to claim 17 wherein in step c) orstep d) or both the solvent is acetone.
 20. A process for preparingcrystalline levosalbutamol sulphate Form III according to claim 9 whichprocess comprises a) preparing levosalbutamol in an organic solvent b)adjusting the pH by addition of sulphuric acid at 25 to 30° C. c)isolating the product (Form III) at 25 to 30° C.
 21. A process accordingto claim 20 wherein the organic solvent is an alcoholic solvent.
 22. Aprocess according to claim 21 wherein the solvent comprises denaturedalcohol or methanol or a mixture of the two.
 23. A process according toclaim 20 wherein in step b) the pH is adjusted to from 5 to 5.5.
 24. Aprocess for preparing crystalline levosalbutamol sulphate Form Iaccording to claim 1, which process comprises a) dissolving any form oflevosalbutamol sulphate in water b) combining the solution from step a)with a water miscible organic solvent so as to cause precipitation c)isolating Form I thereon.
 25. A process according to claim 24 whereinthe water-miscible organic solvent is methanol.
 26. A process accordingto claim 24 wherein prior to step c) the solution is cooled to from 0°C. to 5° C.
 27. A process for preparing crystalline levosalbutamolsulphate Form II according to claim 5, which process comprises jetmilling any other form of levosalbutamol sulphate.
 28. A processaccording to claim 27 wherein crystalline levosalbutamol sulphate Form Iis jet milled to give said Form II.
 29. A process for preparingcrystalline levosalbutamol sulphate Form III according to claim 9, whichprocess comprises a) dissolving any form of levosalbutamol sulphate inwater b) combining the solution from step a) with a water-miscibleorganic solvent so as to cause precipitation c) isolating Form IIItherefrom at ambient temperature.
 30. A process according to claim 29wherein the water-miscible organic solvent is acetone.
 31. A processaccording to claim 29 wherein the process is carried out at from 25° C.to 30° C.
 32. A pharmaceutical composition comprising a compoundaccording to claim 1, and a pharmaceutically acceptable carrier.
 33. Apharmaceutical composition comprising a compound according to claim 1 incombination with one or more pharmaceutically active compounds and,optionally, a pharmaceutically acceptable carrier.
 34. A pharmaceuticalcomposition according to claim 33 wherein the further active compound isone or more of fluticasone propionate, beclomethasone dipropionate,budesonide, ipratropium bromide, ambroxol or theophylline.
 35. Acompound according to claim 1, for use as a medicament.
 36. A compoundor composition according to claim 35 for use in the treatment ofrespiratory disorders and related conditions.
 37. A combinationcomprising a compound according to claim 1 and one or morepharmaceutically active compounds and optionally at least onepharmaceutically acceptable carrier; for simultaneous, separate orsequential use.